The Liver’s Response to Injury : Inflammation and Fibrosis

Introduction

Inflammation is a part of the immune response to infection and trauma, and under physiologic conditions is designed to facilitate wound healing. The traditional inflammatory response is characterized as a complex reaction to an injuring agent that involves the loss of vascular wall integrity, activation of leukocytes and their extravasations, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. The liver functions to eliminate toxins and pathogens from the circulation, and has developed a unique mechanism of immunosurveillance. To avoid unnecessary activation of the immune system, the liver has a local immune response followed by induction of peripheral tolerance toward the antigen. When stressful agents such as pathogens or environmental insults challenge the liver for extended periods and their elimination is not possible, then inflammation follows.

Hepatic fibrosis and then cirrhosis commonly follows chronic inflammation. Sustained suppression of inflammatory activity by elimination of the etiologic agent or by dampening of the immune response can halt and even reverse the fibrotic process. The success of current treatments of chronic liver inflammation in achieving antifibrotic effects can be measured by prolonged survival and possibly a reduced occurrence of hepatocellular carcinoma. Thus hepatic inflammation is one driver of fibrosis, cirrhosis, and hepatocellular carcinoma.

Hepatic Inflammation as a Driver of Hepatic Fibrosis

Liver inflammation is commonly associated with hepatocyte necrosis and apoptosis. These forms of liver cell injury initiate a sequence of events that is independent of the etiologic cause of the inflammation and provide signals for the development of liver fibrosis. Apoptotic hepatocyte bodies can activate quiescent hepatic stellate cells (HSCs) and Kupffer cells, and these activated cell populations in turn promote inflammation and fibrogenesis. The activated HSCs also increase the production of inflammatory chemokines, the expression of adhesion molecules, and the presentation of antigens to T lymphocytes and natural killer T (NKT) cells. These enhanced inflammation and immune responses can promote hepatocyte necrosis and apoptosis and thereby strengthen and perpetuate the stimuli for fibrogenesis.

Transforming growth factor (TGF)-β ₁ and platelet-derived growth factor (PDGF) activate HSCs for transformation into myofibroblasts. Myofibroblasts are characterized immunophenotypically by a spindle or stellate shape, pale eosinophilic cytoplasm, and expression of abundant pericellular matrix and extracellular matrix (ECM) proteins, such as vimentin, alpha smooth muscle actin, nonmuscle myosin, fibronectin, and collagen type I.

There are several potential sources of hepatic myofibroblasts in the liver. HSCs and portal fibroblasts are the liver-resident mesenchymal cells. They are the major source of myofibroblasts in fibrotic liver. On the other hand, bone marrow–derived fibrocytes and mesenchymal progenitor cells may be recruited to the injured liver, where they contribute to inflammation and fibrosis, but are a minor component of the liver myofibroblast population. Primary cell culture studies have clearly demonstrated that cholangiocytes and hepatocytes undergo a change in the phenotype and gene expression toward a mesenchymal cell, especially after incubation with TGF-β, which is the cytokine most closely associated with epithelial-to-mesenchymal transition. However, more recent reports provide strong evidence against epithelial-to-mesenchymal transition in the liver as a source of myofibroblasts. These studies have shown that genetic labeling of hepatocytes (with albumin-Cre mice), cholangiocytes (with cytokeratin 19-Cre mice) and their precursors did not result in generation of myofibroblasts in vivo. The origin of myofibroblasts may reflect the nature of the liver injury and the microenvironment within the liver ( Fig. 5-1 ).

Recent studies have also identified macrophages as critical regulators of fibrosis. As with myofibroblasts, these cells are derived from either resident tissue populations, such as Kupffer cells, or from bone marrow immigrants. Studies now suggest that the pathogenesis of fibrosis is tightly regulated by distinct macrophage populations that exert unique functional activities throughout the initiation, maintenance, and resolution phases of fibrosis. Activated macrophages can not only release chemokines that stimulate HSCs, but can also release reactive oxygen species, nitric oxide, and chemotactic proteins that promote hepatocyte injury and enhance the inflammatory responses. The resultant oxidative stress on the hepatocytes can damage DNA, induce apoptosis, promote the expression of proinflammatory genes, enhance fibrogenesis, and possibly trigger malignant transformation.

The net consequence of these diverse interactive cellular and molecular mechanisms is to extend the tissue injury and enhance the accumulation of the ECM. The accumulation of collagens I and IV, procollagen III, and elastin occurs early in liver injury, and matrix metalloproteinases (MMPs) that are directed at the different types of collagen are activated to degrade the depositions and maintain stability of the matrix. Tissue inhibitors of metalloproteinases are also expressed to counterregulate the degradation process. Maturation of the collagen matrix depends mainly on lysyl oxidases, which cross-link the collagen fibrils and increase the resistance to degradation.

Although the inflammatory process is geared toward tissue repair, healing, and disposal of infectious agents, its effects are widespread and potentially harmful. It is this conflicting aspect of inflammation that is frequently referred to as a double-edged sword or the friend or foe? nature of inflammation. Chronic inflammation can exist as a result of the failure of host mechanisms to terminate an acute inflammation. Unlike the acute setting, where the cellular players are predominantly neutrophils, chronic inflammatory infiltrates are typified by mononuclear cells such as macrophages, lymphocytes, and plasma cells. The persistence of these cells can result in further tissue damage and trigger a wound-healing response in the form of angiogenesis and fibrosis. Hepatic inflammation initiates fibrogenesis by promoting hepatocyte necrosis and apoptosis, sustains fibrogenesis by activating HSCs and Kupffer cells, and maintains itself by the actions of proinflammatory cytokines and chemokines that influence the trafficking of inflammatory and immune cells within the liver.

Cell Types That Participate in Inflammation and Fibrosis